Twenty years of experience using trigger films as a teaching tool.

Trigger films or trigger videos that depict patient-physician encounters can be used to provoke reflection, stimulate discussion, help learners confront their feelings and give learners practice in responding to challenges. For more than 20 years at the B. Rappaport Faculty of Medicine, the authors have used trigger films to teach/demonstrate the doctor-patient relationship, medical ethics, diagnostic thinking, professional behavior, and the application of the principles of the Israeli Patient Bill of Rights, and have found them to be an excellent tool for provoking active participation in small-group discussions. The authors describe how they have effectively produced and used trigger films in an Introduction to Clinical Medicine course. They highly recommend the "homemade" production of trigger films.

Extracellular calcium modulates persistent sodium current-dependent burst-firing in hippocampal pyramidal neurons.

The generation of high-frequency spike bursts ("complex spikes"), either spontaneously or in response to depolarizing stimuli applied to the soma, is a notable feature in intracellular recordings from hippocampal CA1 pyramidal cells (PCs) in vivo. There is compelling evidence that the bursts are intrinsically generated by summation of large spike afterdepolarizations (ADPs). Using intracellular recordings in adult rat hippocampal slices, we show that intrinsic burst-firing in CA1 PCs is strongly dependent on the extracellular concentration of Ca(2+) ([Ca(2+)](o)). Thus, lowering [Ca(2+)](o) (by equimolar substitution with Mn(2+) or Mg(2+)) induced intrinsic bursting in nonbursters, whereas raising [Ca(2+)](o) suppressed intrinsic bursting in native bursters. The induction of intrinsic bursting by low [Ca(2+)](o) was associated with enlargement of the spike ADP. Low [Ca(2+)](o)-induced intrinsic bursts and their underlying ADPs were suppressed by drugs that reduce the persistent Na(+) current (I(NaP)), indicating that this current mediates the slow burst depolarization. Blocking Ca(2+)-activated K(+) currents with extracellular Ni(2+) or intracellular chelation of Ca(2+) did not induce intrinsic bursting. This and other evidence suggest that lowering [Ca(2+)](o) may induce intrinsic bursting by augmenting I(NaP). Because repetitive neuronal activity in the hippocampus is associated with marked decreases in [Ca(2+)](o), the regulation of intrinsic bursting by extracellular Ca(2+) may provide a mechanism for preferential recruitment of this firing mode during certain forms of hippocampal activation.

Disseminated fat necrosis with asymptomatic pancreatitis: a case report and review of the literature.

A 62-year-old man with multiple nontender skin nodules is presented. Some of these nodules discharged a purulent looking fluid. At presentation, the patient did not have any other complaints. No infectious, neoplastic, or immunologic origin could be found for the nodular rash. Biochemical profile, imaging, and skin biopsy confirmed the diagnosis of disseminated fat necrosis (DFN) accompanying asymptomatic pancreatitis. The process involved the mesenteric, subcutaneous, and intramedullary fat. The skin lesions were surgically treated. Mesenteric and intramedullary fat necrosis were watched closely. A year later, the patient was readmitted with a diagnosis of pancreatitis. Subcutaneous and intramedullary necrosis were completely resolved at this time, and only mesenteric fat necrosis prevailed. The clinical syndrome of DFN, its etiology, pathophysiology, treatment, and prognosis are discussed.

A multidisciplinary forum for ethics in medicine: our seven years experience.

The Rappaport Faculty of Medicine of the Technion established an Ethics in Medicine Forum in March 1993. The main objective of the forum was to increase awareness of the philosophical principles of ethics in medicine, as defined and developed in the western world during the last three decades. The multidisciplinary forum meets once a month during the academic year. Our 7 years experience is documented. Of the 45 meetings, 30 were clinically oriented and of these more than half were based on cases. Only 15 meetings were purely theoretical. Our principal assumption was that any and every topic could be discussed, including those covered by the law. We explored how well western philosophical principles and rules fit the Israeli picture. Many of the forum discussions related to the draft of the Patient's Bill of Rights, which came into effect on 12 May 1996. The role of the "legal" hospital ethics committees was compared to that of the "advisory" ethics committees whose members constituted a large share of our forum. The multicultural Israeli population and the practice of medicine therein raised many lively discussions. The principle of autonomy in the ultraorthodox and in the family setting was a highly controversial issue. The forum served as a workshop for examining traditional medical ethical principles, which we strongly feel needs to be amended in light of the 1996 Patient's Bill of Rights. From our 7 years experience with an Ethics in Medicine Forum we recommend that medical ethical deliberations focus on genuine medical cases.

Ascites and pleural effusion secondary to extramedullary hematopoiesis.

Extramedullary hematopoiesis in the pleura and peritoneum is rare. It is usually asymptomatic and generally is diagnosed on post mortem examination. Herein we describe a 33-year-old woman with long-standing myelofibrosis who presented with symptomatic ascites and pleural effusion. After complete evaluation, these were found to have been caused by extramedullary hematopoietic implants to the pleura and peritoneum. The pleural effusion responded to low-dose radiotherapy.

Protein kinase C mediates muscarinic block of intrinsic bursting in rat hippocampal neurons.

1. Acetylcholine released from basal forebrain cholinergic fibres suppresses intrinsic bursting in cortical pyramidal cells through activation of muscarinic receptors. The signal transduction pathway mediating this action is not known. We used intracellular recordings from CA1 pyramidal cells in hippocampal slices to investigate the involvement of protein kinase C (PKC) in this cholinergic function. 2. Bath-applied carbachol (CCh; 5 microM) consistently suppressed intrinsic bursting in an atropine-sensitive (1 microM) manner. 3. Intrinsic bursting was suppressed by 4beta-phorbol 12,13-dibutyrate (PDBu; 5-10 microM), a potent PKC activator, but not by the inactive phorbol ester 4alpha-phorbol 12,13-didecanoate (PDC; 50 microM). Prior application of the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7; 10 microM) extracellularly or intracellularly prevented the PDBu effect. 4. Pretreatment with H7, but not with the broad-spectrum kinase inhibitor N-(2-guanidino-ethyl)-5-isoquinoline-sulfonyl hydrochloride (HA1004; 10 microM), prevented the CCh-induced suppression of bursting. 5. The active component of the spike after-depolarization (ADP) was reduced by CCh in an atropine-sensitive manner. This effect was mimicked by PDBu, but not by PDC. It was prevented by pretreatment with H7, but not with HA1004. 6. Blocking most K+ currents with Ca2+-free, TEA-containing saline induced large TTX-sensitive plateau potentials lasting > 150 ms, driven by a persistent Na+ current. These potentials were suppressed by PDBu, but not by PDC. Pretreatment with H7 prevented the PDBu-induced suppression of the plateau potentials. 7. We conclude that cholinergic suppression of intrinsic bursting in hippocampal CA1 pyramidal cells is mediated by muscarinic activation of PKC, which down-regulates the persistent Na+ current underlying slow depolarizing potentials in these neurons.

Modulation of endogenous firing patterns by osmolarity in rat hippocampal neurones.

1. Intracellular recordings in adult rat hippocampal slices were used to investigate the modulation of endogenous neuronal firing patterns by moderate changes (+/-13%) in the extracellular osmotic pressure (pi o). The responses of CA1 pyramidal cells to graded depolarizing current pulses were used to differentiate between regular and burst-firing patterns and to characterize the stimulus requirements for evoking endogenous burst discharge. 2. Decreasing or increasing pi o had no significant effects on resting membrane potential and input resistance, spike threshold and amplitude, and the amplitudes of the fast, medium and slow spike after-hyperpolarizations (AHPs). The apparent membrane time constant (tau m) increased in low pi o and decreased in high pi o. 3. Reducing pi o converted non-bursting neurones (non-bursters) to bursting neurones (bursters) and decreased the stimulus requirements for evoking burst firing in native bursters. Increasing pi o suppressed endogenous burst firing. 4. Lowering pi o increased the size of the 'active' (i.e. re-depolarizing) component of the spike after-depolarization (ADP). Conversely, increasing pi o suppressed the active ADP component. 5. The sensitivity of spike ADPs and firing patterns of pyramidal cells to the changes in pi o persisted also in Ca(2+)-free saline, indicating that the osmotic effects are not imparted by modulation of Ca2+ and/or Ca(2+)-activated K+ currents. 6. Blocking most K+ currents with Ca(2+)-free, TEA-containing saline induced large and prolonged (up to 1 s), TTX-sensitive plateau potentials following the primary fast spikes. These potentials were augmented by low pi o and abated by high pi o. 7. When injected with subthreshold depolarizing current pulses in Ca(2+)-free saline, pyramidal cells displayed a distinct TTX-sensitive inward rectification. This rectification was augmented by low pi o and reduced by high pi o. 8. The various effects of low-pi o and high-pi o saline solutions were reversible upon washing with normosmotic saline. 9. We conclude that pi o is a critical determinant of the endogenous firing patterns of CA1 pyramidal cells. The data suggest that the osmotic effects are most likely to be mediated by changes in the persistent Na+ current, which underlies the active spike ADP and the burst potential in CA1 pyramidal neurones. The possible contribution of these effects to changes in brain excitability in various abnormal osmotic states in discussed.

Menstrual asthma: use of a gonadotropin-releasing hormone analogue for the treatment of cyclic aggravation of bronchial asthma.

A new clinical indication for GnRH-a treatment seems to exist in addition to the many indications known so far. The successful treatment of cyclic severe attacks of bronchial asthma during ovulation and the menstrual periods with a GnRH-a is described. A 45-year-old woman with long-standing bronchial asthma was hospitalized because of severe bronchial asthma and status asthmaticus 11 times during the 5 months before her referral. The hospitalizations were either during the ovulatory or menstrual period, and in two of them they were so grave to require artificial ventilation through an endotracheal tube. To induce pituitary-ovarian desensitization and amenorrhea, the patient was put on monthly injections of depot GnRH-a, which she has been receiving for the last 20 months. Subjective improvement was accompanied by a significant improvement in spirometric indices, by lack of hospitalizations, and decrease in glucocorticoid daily dosage. Although a trial of sequential add-back HRT was unsupportable because of respiratory aggravation, low-dose continuous HRT was tolerated by the patient. In light of the dramatic subjective and objective improvement in association with the GnRH-a treatment, we conclude that this new application deserves further experience.

Bronchiolitis obliterans organizing pneumonia. Diagnosis by transbronchial biopsy.

Transbronchial biopsy (TBB) has been considered to be inadequate for the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP). We describe herein two patients with interstitial pulmonary disease in whom the diagnosis of BOOP was achieved by TBB. The two patients presented with progressive dyspnea, cough, tachypnea, and fine end-inspiratory crackles. The radiologic findings disclosed patchy alveolar infiltrates. Pulmonary function tests showed a restrictive pattern and decreased diffusing capacity. The pathologic findings disclosed bronchioles, alveolar ducts, and alveoli infiltrated with mononuclear cells. The lumina were obliterated with fibroblasts and loose granulation tissue. Corticosteroid treatment resulted in significant improvement. Transbronchial biopsy should be considered as a useful diagnostic tool for BOOP.

Monoclonal antibodies to the heavy neurofilament subunit (NF-H) of Torpedo cholinergic neurons.

Previous studies from our laboratory suggest that Alzheimer's disease sera contain a repertoire of antibodies to the heavy neurofilament subunit (NF-H) and that a subpopulation of these antibodies bind specifically to epitopes highly enriched in NF-H isolated from the purely cholinergic electromotor neurons of Torpedo. In the present study, we prepared and characterized monoclonal antibodies (MAbs) that bind to epitopes specifically enriched in Torpedo cholinergic neurons. This was performed by a differential enzyme-linked immunosorbent assay (ELISA) in which MAbs were selected that bind to epitopes much more abundant in the NF-H protein of Torpedo cholinergic neurons than in NF-H from the chemically heterogeneous Torpedo spinal cord. This yielded four MAbs, three of which (TC4, TC8, and TC21) were found to be specific to NF-H and one (TC15) that reacts with both NF-H and the medium-size neurofilament subunit NF-M. Dephosphorylation abolishes the binding of MAbs TC4 and TC15 to Torpedo cholinergic NF-H, partially reduces that of MAb TC21 and has no effect on the binding of MAb TC8. This suggests that the antigenic sites specific to Torpedo cholinergic NF-H contain phosphorylated as well as non phosphorylated epitopes. All the MAbs cross-react with rat brain NF-H.

Induction of cognitive deficits by immunization with cholinergic cell bodies: the influence of age and integrity of the blood-brain barrier.

We have recently shown that prolonged immunization of young rats for one year with cholinergic cell bodies (perikarya, PK) purified from Torpedo electric lobe results in the accumulation of IgG in specific brain areas such as the hippocampus and induces behavioral deficits in spatial orientation and short term memory /1, 7/. We presently studied the rate of development of the cognitive deficit in older (12 months old) Sprague Dawley rats which were immunized for periods of up to one year with either Torpedo cholinergic PK or adjuvant (controls). T-maze alternation and Morris swim maze tests revealed a small deficit in the performance of the PK immunized rats after 6 months whereas significant deficits were observed after 12 months of immunization. These results suggest that the duration of immunization is a more significant factor than the age of the animals in the development of the behavioral deficit. In order to examine whether permeability of the blood-brain barrier to IgG influences the rate of development of the cognitive deficit, we disrupted the blood-brain barrier of PK immunized rats by hypercapnia. This treatment repeated weekly for 2 months was found not to accelerate the rate of appearance of deficits in performance of the rats in the T-maze alternation and Morris swim test. These results suggest that penetration of IgG via the blood-brain barrier does not determine the rate of appearance of the cognitive deficits.

Anti-neuronal antibodies similar to those found in Alzheimer's disease induce memory dysfunction in rats.

Although the etiology and pathogenesis of the cholinergic degeneration in Alzheimer's disease are not known, several reports implicate immunological mechanisms. Recently we have shown that sera of Alzheimer's disease patients contain antibodies which bind specifically to the heavy molecular weight neurofilament protein of Torpedo cholinergic neurons. In the present study we investigated the possibility that such antibodies play a role in neuronal degeneration by examining the behavioral and cellular effects of immunizing rats with the heavy neurofilament protein of Torpedo cholinergic neurons. The immunized rats developed antibodies which were specific to the heavy neurofilament protein of Torpedo cholinergic neurons and which cross-reacted with rat brain neurofilaments. Immunohistochemical studies revealed the accumulation of antibodies in the perikarya and neurites of neurons in the septum and hippocampus of the cholinergic neurofilament immunized rats and in white matter tracts in their forebrains. No such staining was seen in adjuvant immunized control rats. Behavioral tests revealed that rats immunized with the heavy cholinergic neurofilament protein performed significantly worse than controls in a T-maze alternation test and that their performance deteriorated profoundly after the introduction of a 20-s delay in the paradigm, indicating a deficit in short term memory. In contrast, both groups performed similarly in a T-maze discrimination test, indicating that long term reference memory was not affected by immunization with the heavy cholinergic neurofilament protein. Further experiments revealed that the rats immunized with the heavy cholinergic neurofilament protein were also deficient in a reversal of choice paradigm in a position discrimination test.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of an experimental autoimmune dementia model in the rat.

Alzheimer's disease (AD) and other age-related cognitive deficits are associated with autoimmune phenomena. We recently showed that AD sera contain IgG that binds specifically to the heavy molecular weight neurofilament protein (NF-H) of Torpedo cholinergic neurons. We presently examined the behavioral effects of the induction of such antibodies in rats by prolonged immunization with Torpedo cholinergic NF-H. Immunohistochemical studies revealed the accumulation of IgG in the septum and hippocampus and in white matter tracts of these rats. T-maze alternation and discrimination tests revealed that immunization impaired the short-term working memory of the rats but had no effect on their reference memory. This impairment in short-term memory was reversed by treatment with the acetylcholinesterase inhibitor physostigmine. This animal model, termed experimental autoimmune dementia (EAD), may replicate immunologically induced pathogenic processes in AD.

Total digoxin-like immunoreactive factor(s) in healthy population, uncomplicated term pregnancies and neonates.

Free digoxin-like immunoreactive factor(s) (DLIF) which may have a homeostatic role, as documented in different physiological conditions, but is generally undetectable in plasma from normal population. Total digoxin-like immunoreactive factor(s) (protein bound and free) can be estimated after plasma is heated. In this study, total digoxin-like immunoreactive factor(s) as measured in plasma in a well defined control population and compared to healthy term pregnant women and neonates, categories known to be associated with increased free digoxin-like immunoreactive factor(s) concentrations. The mean level of this factor(s) in the control group was 706 +/- 129 pg digoxin equivalent/ml (pg/ml) and was unaffected by age and sex. Significantly increased levels of total digoxin-like immunoreactive factor(s) were found in pregnant women and neonates (928 +/- 127 and 1242 +/- 367 pg/ml, respectively). We conclude that levels of total digoxin-like immunoreactive factor(s) are increased in term pregnancies and neonates, similarly to its free form. However total digoxin-like immunoreactive factor(s) is detected in the normal population as a plasma component, contrary to its free form, which is generally undetectable.